Implants are utilized in modern medical technology in a variety of applications. They are used e.g. to support vessels, hollow organs, and ductal systems (endovascular implants e.g. stents), to fasten and temporarily fix tissue implants and tissue transplants in position, as well as for orthopedic purposes such as pin, plate, or screw. The stent is a form of an implant that is used particularly frequently.
Stent implantation has been established as one of the most effective therapeutic measures for treating vascular disease. Stents may be used to provide support in a patient's hollow organs. To this end, some stents have a filigree support structure composed of metallic struts that are initially present in a compressed form for insertion into the body, and are expanded at the application site. One of the main applications of stents of this type is to permanently or temporarily widen and hold open vasoconstrictions, including constrictions (stenoses) of the coronary arteries. In addition, aneurysm stents are known, for example, which are used to support damaged vascular walls.
Some stents include a circumferential wall, providing support that suffices to hold the constricted vessel open to a desired extent, and a tubular base body through which blood continues to flow without restriction. The circumferential wall can be formed by a latticed support structure that enables the stent to be inserted in a compressed state, having a small outer diameter, until it reaches the constriction in the particular vessel to be treated, and to be expanded there, e.g. using a balloon catheter, to the extent that the vessel has the desired, increased inner diameter.
An implant, for example a stent, has a base body composed of an implant material. An implant material is a nonliving material that is used for a medical application and interacts with biological systems. A prerequisite for the use of a material as an implant material that comes in contact with the body environment when used as intended is its biocompatibility. “Biocompatibility” refers to the capability of a material to evoke an appropriate tissue response in a specific application. This includes an adaptation of the chemical, physical, biological, and morphological surface properties of an implant to the recipient tissue, with the objective of achieving a clinically desired interaction. The biocompatibility of the implant material may also be dependent on the time sequence of the response of the biosystem in which the implant is placed. For example, irritations and inflammations, which can cause tissue changes, occur over the relative short term. Biological systems therefore respond differently depending on the properties of the implant material. Depending on the response of the biosystem, implant materials can be subdivided into bioactive, bioinert, and degradable/resorbable materials.
Implant materials include polymers, metallic materials, and ceramic materials (as coating, for example). Biocompatible metals and metal alloys for permanent implants contain e.g. stainless steels (e.g. 316L), cobalt-based alloys (e.g. CoCrMo casting alloys, CoCrMo forging alloys, CoCrWNi forging alloys, and CoCrNiMo forging alloys), pure titanium and titanium alloys (e.g. CP titanium, TiAl6V4 or TiAl6Nb7), and gold alloys. In the field of biocorrodible stents, the use of magnesium or pure iron and biocorrodible base alloys of the elements magnesium, iron, zinc, molybdenum, and tungsten is proposed.
A biological response to polymeric, ceramic, or metallic implant materials depends on the concentration, duration of exposure, and type of supply. The presence of an implant material may evoke inflammatory responses which can be triggered by mechanical irritations, chemical substances, or metabolites. The inflammatory process is typically accompanied by the immigration of neutrophil granulocytes and monocytes through the vascular walls, the immigration of lymphocyte effector cells with the formation of specific antibodies to the inflammatory stimulus, activation of the complement system with the release of complement factors which act as mediators, and, ultimately, activation of blood coagulation. An immunological response is usually closely associated with the inflammatory response and can lead to sensitization and the development of allergies. Known metallic allergens include e.g. nickel, chromium, and cobalt which are also used in many surgical implants as alloying constituents. A main problem associated with the implantation of a stent in a blood vessel is in-stent restenosis due to excessive neointimal growth caused by a strong proliferation of arterial smooth muscle cells and a chronic inflammatory response.
A greater level of biocompatibility can be achieved by coating implant materials with particularly tissue-compatible materials. These materials are usually organic or synthetic polymeric in nature and are partially of natural origin. Further strategies for preventing restenosis focus on inhibiting proliferation using medication, for example, treatment using cytostatic agents. The active ingredients can be provided on the implant surface in the form of a coating.
The RGD triad (Arg-Gly-Asp) serves many integrins as a primary recognition site for proteins of the extracellular matrix. Peptides that contain this sequence can therefore mimic the ligands of these integrins and bind thereto. Linear RGD peptides display a low affinity to many integrins, but a head-to-tail cyclization of pentapeptides results in a conformational constriction, thereby increasing the capability to bind to some integrins. Peptides that bind selectively to certain integrins or integrin groups and therefore inhibit them can be synthesized by selecting the amino acids that flank the RGD sequence such that this objective is met. Due to the fact that RGD peptides are selective antagonists for integrins, their medical relevance—or the medical relevance of peptidomimetics derived therefrom—is the subject of research. For example, the integrin ανβ3, which is expressed by tumor cells very frequently and plays a key role in the mechanism of invasive tumor growth, is well-inhibited by the peptide c(RGDfV). Furthermore, cRGD peptides are used as inhibitors for angiogenesis in tumor diseases, and in osteoporosis.
In terms of developing implants coated with active ingredients, in particular stents coated with active ingredients (which are referred to as DES stents), the use of cRGDs is a proposed approach to improving the compatibility of implants. Mainly, however, cRGDs can be used to improve the healing process. To achieve a long-term antiproliferative effect, however, it is usually necessary to release other active ingredients, for example, rapamycin, from the coating. Adding cRGD subsequently to an existing coating system therefore creates the problem of ensuring that cRGDs are provided on the surface of the implant at the earliest possible point in time, while ensuring that the elution characteristic of an active ingredient contained in a base of the coating underneath the surface does not change. Otherwise, the elution characteristic of the active ingredient would have to be re-optimized, which is very difficult to do in isolated cases, and which makes it difficult to vary the system.